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J. Biol. Chem., Vol. 281, Issue 1, 638-647, January 6, 2006

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The Related Retinoblastoma (pRb) and p130 Proteins Cooperate to Regulate Homeostasis in the Intestinal Epithelium^*

Kevin Haigis1, Julien Sage2, Jon Glickman¶, Sarah Shafer, and Tyler Jacks, An investigator of the Howard Hughes Medical Institute||3

From the Department of Biology and the Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, ^¶Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, and ^||Howard Hughes Medical Institute, Chevy Chase, Maryland 20185

pRb, p107, and p130 are related proteins that play a central role in the regulation of cell cycle progression and terminal differentiation in mammalian cells. Nevertheless, it is still largely unclear how these proteins achieve this regulation in vivo. The intestinal epithelium is an ideal in vivo system in which to study the molecular pathways that regulate proliferation and differentiation because it exists in a constant state of development throughout an animal's lifetime. We studied the phenotypic effects on the intestinal epithelium of mutating Rb and p107 or p130. Although mutating these genes singly had little or no effect, loss of pRb and p107 or p130 together produced chronic hyperplasia and dysplasia of the small intestinal and colonic epithelium. In Rb/p130 double mutants this hyperplasia was associated with defects in terminal differentiation of specific cell types and was dependent on the increased proliferation seen in the epithelium of mutant animals. At the molecular level, dysregulation of the Rb pathway led to an increase in the expression of Math1, Cdx1, Cdx2, transcription factors that regulate proliferation and differentiation in the intestinal epithelium. The absence of Cdx1 function in Rb/p130 double mutant mice partially reverted the histologic phenotype by suppressing ectopic mitosis in the epithelium. These studies implicate the Rb pathway as a regulator of epithelial homeostasis in the intestine.

Received for publication, June 16, 2005 , and in revised form, October 25, 2005.

^* This work was supported by a grant from the NCI, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A Robert Black Fellow of the Damon Runyon Cancer Research Foundation.

² Supported by a fellowship from the Medical Foundation.

³ To whom correspondence should be addressed: Center for Cancer Research, MA Institute of Technology, E17-517A, 77 Massachusetts Ave., Cambridge, MA 02139. Tel.: 617-253-0262; Fax: 617-253-9863; E-mail: tjacks{at}mit.edu.

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